Project Summary ? Center on the Physics of Cancer Metabolism Despite advances in breast cancer treatment, metastatic disease remains incurable and is of particular concern in patients with triple negative breast cancer (TNBC). Both aberrant metabolic signaling and physical properties of the microenvironment have been independently defined as hallmarks of cancers, and limited experimental evidence suggests that they may be functionally linked. However, the current of lack of physiologically relevant culture models that capture relevant physical details prevents studying the specific mechanisms that link metabolic reprogramming, the physical microenvironment, and clinical outcomes of malignancy. By leveraging capabilities of six different institutions (Cornell University Ithaca, Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, Purdue University, University of California San Francisco) the proposed Physical Sciences Oncology Center (PSOC) will apply physical science approaches to interrogate the multiscale biological and physical (structural, mechanical, and solute transport) mechanisms regulating tumor metabolism and function, as well as the consequences on tumor development, metastatic progression, and therapy response. This work will be addressed using three research projects that test the physical mechanisms by which the microenvironment regulates tumor metabolism and how obesity affects this interplay (Project 1), investigate the role of altered metabolism and the physical microenvironment in modulating the biogenesis and function of microvesicles (Project 2), and evaluate the integrated effects of physical and metabolic constraints on tumor cell migration and invasion (Project 3). These projects will be supported by two Cores that will provide computational modeling and microfabricated, patient-derived culture platforms with physiologically relevant metabolic stresses, mechanical cues, and transport phenomena (Core 1: Tissue Microfabrication Core) and will assist investigators in state-of-the-art imaging analysis of cellular metabolic state, microvesicle characterization, and nanoscale cellular properties (Core 2: Biophysics and Imaging Core). The research activities of our Center will be enhanced by an Education and Outreach Unit that will train interdisciplinary cancer researchers who are able to effectively engage across multiple sectors (academia, industry, government) to move treatment forward. All activities will be coordinated through an Administrative Core that will foster synergy and integration within the Center and with the overall Physical Sciences Oncology Network (PSON). Collectively, our proposed PSOC will generate physical sciences-driven mechanistic insights in the context of precision medicine approaches with the ultimate promise of improving clinical outcomes. While our initial focus will be on TNBC, it is our long-term goal to test the broad applicability of our findings to other subtypes of cancer as well as metastatic prostate cancer and pancreatic cancer thus, further advancing the overall impact of our Center.